N-Substituted aziridine-2-carboxylic acid derivatives and their immuno-stimulation compositions and methods

ABSTRACT

A 2-cyanaziridine derivative of the formula ##STR1## wherein R&#39; is a straight-chained or branched, saturated or mono- or polyunsaturated aliphatic hydrocarbon radical with up to 8 carbon atoms, which is substituted by an aromatic nitrogen-containing heterocyclic radical with 5 or 6 ring-members and 1, 2 or 3 nitrogen atoms optionally substituted by halogen, alkoxy with up to 8 carbon atoms, alkyl with up to 8 carbon atoms, hydroxyl, carbalkoxy with up to 9 carbon atoms, carbamoyl, dialkylamino the alkyl moieties of which having up to 8 carbon atoms, cycloalkylamino, the cycloalkyl moiety having 3-10 carbon atoms, acetylamino, nitro, cyano, acetyl, alkylthio with up to 8 carbon atoms, alkylsulphinyl with up to 8 carbon atoms, alkylsulphonyl with up to 8 carbon atoms, sulphamoyl, phenyl, trifluoromethyl, phenoxy, acetoxy or methylenedioxy; 
     or a pharmacologically acceptable salt thereof, exhibits immune stimulating activity.

This is a continuation-in-part of application Ser. No. 59,863 filed July23, 1979, now U.S. Pat. No. 4,321,194.

The present invention is concerned with pharmaceutical compositionscontaining N-substituted aziridine-2-carboxylic acid derivatives, someof which are new, and with the preparation of such N-substitutedaziridine-2-carboxylic acid derivatives.

It is known that aziridines, because of their structure and properties,belong to the alkylating-acting compounds, for example cyclophosphamideand N-lost compounds, which play an important part in the therapy ofcancer. Unfortunately, the alkylating action does not take placeselectively with the components of the cancer cells so that thesecompounds can also act cancerogenically on normal cells. However,substitution with a cyano group in the 2-position of the aziridine ringsshowed that the ability to alkylate and thus also the toxicity was lost.

German Democratic Republic Patent Specification No. 110,492 describes1-carbamoyl-2-cyanoaziridine which, when administered intravenously torats, bring about a very marked increase of the leukocytes andlymphocytes, whereas the number of erythrocytes remains almostunchanged. Furthermore, a considerable multiplication of theantibody-forming spleen cells was observed. Therefore, this compound canbe used as an immune-stimulating therapeutic in cases of bacterial andviral infections (see Federal Republic of Germany Patent SpecificationNo. 25 28 460.0). However, the low stability of this compound insolution and the complete ineffectiveness when administered orallyproved to be serious disadvantages of this compound.

Therefore, the problem exists of finding immune-stimulating therapeuticcompounds which, with the same or increased effectiveness and lowtoxicity, do not display any noteworthy side effects, are more stableand can be more simply administered, preferably orally.

We have now found that this problem is solved by a class ofaziridine-2-carboxylic acid derivatives which are substituted on thering nitrogen atom by alkyl or aryl radicals.

Thus, according to the present invention, there are providedpharmaceutical compositions containing at least oneaziridine-2-carboxylic acid derivative which is substituted on the ringnitrogen atom and which have the general formula: ##STR2## wherein X isa carboxyl or nitrile group or an alkoxycarbonyl radical or anunsubstituted or substituted carbamoyl group; R is a straight-chained orbranched, saturated or mono- or poly-unsaturated aliphatic hydrocarbonradical which is optionally substituted one or more times by halogen,alkoxy, hydroxyl, dialkylamino, cycloalkylamino, acylamino, acyl, nitro,alkylthio, alkylsulphinyl, alkylsulphonyl, nitrile, carbalkoxy orcarbamoyl radicals or by cycloalkyl radicals optionally substituted byalkyl, alkoxy or carbalkoxy, or by cycloalkenyl radicals, which canoptionally be bridged, or by an aliphatic or aromatic heterocyclicradical, by aryl, aryloxy, arylthio, acyloxy, alkoxycarbonylamino orureido groups, or R is a cycloalkyl or cycloalkenyl radical containing 3to 10 carbon atoms which is optionally substituted by alkyl, alkoxy,alkoxycarbonyl or oxo groups and is also optionally interrupted byhetero atoms and optionally bridged by 1 to 3 carbon atoms, or R is anaryl or hetaryl radical, the aryl and hetaryl radicals being optionallysubstituted by halogen, alkoxy, alkyl, hydroxyl, carbalkoxy, carbamoyl,dialkylamino, cycloalkylamino, acylamino, nitro, cyano, acyl, alkylthio,alkylsulphinyl, alkylsulphonyl, sulphamoyl, phenyl, trifluoromethyl,aryloxy, acyloxy or methylenedioxy; and R₁ is a hydrogen atom or asaturated, straight-chained or branched alkyl radical containing up to 4carbon atoms or a phenyl radical; and/or at least onepharmacologically-acceptable salt thereof, in admixture with a solid orliquid pharmaceutical diluent or carrier.

The immune stimulation of these compounds of general formula (I) wasdemonstrated by:

1. an increase of the leukocytes and lymphocytes after oral andintravenous administration thereof;

2. an increase of the lymphocyte transformation, measured with the useof the incorporation of radioactively-marked thymidine into humanlymphocytes after incubation with the above-mentioned compounds (see K.Resch in "Praxis der Immunologie", ed. K. O. Vorlaender, pub.Thieme-Verlag, Stuttgart, 1976);

3. the use of animal experimental infection in mice in which it waspossible to show that the additional administration of theabove-mentioned compounds to known bacteriostatically-actingchemotherapeutic compounds, for example chloramphenicol, produced aclearly improved therapeutic effect in comparison with the soleadministration of the bacteriostatic chemotherapeutic, for example,chloramphenicol.

Consequently, the present invention also provides pharmaceuticalcompositions which, in addition to containing at least one compound ofgeneral formula (I) and an appropriate carrier, also contain at leastone known chemotherapeutic agent.

A chemotherapeutic agent is generally to be understood to be a substancewith an antimicrobial action, for example a penicillin or cephalosporincompound, as well as a compound of the nitrofuran group.

The synergistic effect is shown, for example, in the case of apharmaceutical combination which contains an immune stimulant compoundof general formula (I) and the bacteriostatically-actingchemotherapeutic compound chloramphenicol.

The present invention includes within its scope all stereoisomericcompounds of general formula (I) which, for example, exist because ofasymmetric carbon atoms or of cis-trans isomerism, the separation ofwhich into the stereoisomeric forms can be carried out by knownprocesses.

The term "alkyl", if not stated otherwise, is to be understood to mean,alone or in combination, for example in alkoxy, alkoxycarbonyl,N-alkylamino, alkylthio, alkylsulphinyl and alkylsulphonyl radicals, astraight-chained or branched chain containing up to 8 carbon atoms.Preferred alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, sec.-butyl, tert.-butyl, n-pentyl, neo-pentyl and n-hexylradicals. The alkyl chain can optionally be substituted by, for example,halogen, such as chlorine, or by hydroxyl, nitro or cyano. Furthersubstituents which can be present include amino groups, preferablydimethylamino and 2-cyanoaziridin-1-yl radicals, acylamino radicals, forexample, formamido, acetamido and benzamido radicals, and carbamoyl,carbalkoxy and alkoxy radicals.

The mono- and poly-unsaturated aliphatic hydrocarbon radicals are to beunderstood to be radicals which contain 3 to 8 and preferably 3 to 5carbon atoms, with at least one double and/or triple bond in any desiredposition of the unsaturated chain, preferred radicals of this typeincluding the vinyl, allyl, methallyl, crotyl, 2-methylpropenyl,propargyl, but-2-ynyl, but-3-ynyl and pent-3-enyl radicals.

The cycloalkyl and cycloalkenyl radicals are to be understood to bethose containing 3 to 10 carbon atoms, especially the cyclopropyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptenyl and3,6-dioxo-1,4-cyclohexadienyl radicals, as well as cycloalkyl radicalsbridged with 1 to 3 carbon atoms, for example the norbornyl andadamantyl radicals. The cycloalkyl and cycloalkenyl radicals interruptedby hetero atoms are preferably the tetrahydrofuryl, tetrahydropyranyl,thienyl, optionally substituted piperidinyl, morpholinyl andpyrrolidinyl radicals, as well as the N-methyl-3,4-dehydropiperidinyland the N-methyl-piperazinyl radicals.

The aryl radicals, alone or in combination, for example in aryloxy andarylthio radicals, are aromatic carbocyclic radicals and preferablyphenyl, naphthyl, anthracenyl, phenanthrenyl and fluorenyl radicals.

By hetaryl radicals, there are to be understood aromatic ring systemscontaining 5 or 6 members and one or more hetero atoms, for example,oxygen, sulphur or alkylated or acylated nitrogen, which can also becondensed with one or two benzene rings or with another heterocycle.Preferred radicals of this type include the pyridyl, quinolyl, furyl,thienyl, benzofuryl, imidazolyl, pyrazolyl, thiazolyl, pyrimidinyl,pyridazinyl, s-triazolyl, s-triazinyl and purinyl radicals.

The halogen atoms are to be understood to be fluorine, chlorine andbromine atoms.

By acyl radicals there are to be understood, alone or in combination,for example in acyloxy radicals, the acid residues of organic carboxylicand sulphonic acids, preferred radicals of this type including theformyl, acetyl, benzoyl, furoyl, tosyl and methanesulphonyl radicals.

In all cases, the aryl and hetaryl radicals can be substituted one ormore times by the above-mentioned substituents.

When X is a carbamoyl group, it can be optionally substituted by loweralkyl, cycloalkyl, aryl and acyl radicals.

Some of the compounds of general formula (I), in which R₁ is a hydrogenatom or a methyl or phenyl radical and X is a cyano group or analkoxycarbonyl radical, are known from the literature. Thus, forexample, the lower N-alkyl-2-cyanoaziridines, the alkyl radical of whichis unsubstituted, 1-benzyl-2-cyanoaziridine and the like, have beendescribed by Gundermann et al. (Chem. Ber., 105, 312-315). Othercompounds have been described in Federal Republic of Germany PatentSpecification No. 25 30 960. All the known compounds have been describedas intermediates without any mention of a pharmacological effectivenessso that it was surprising that these compounds also have animmune-stimulating action.

The present invention also provides new compounds of the generalformula: ##STR3## wherein X is a carboxy or nitrile group or analkoxycarbonyl radical or an unsubstituted or substituted carbamoylgroup, R' is a straight-chained or branched, saturated or mono- orpolyunsaturated aliphatic hydrocarbon radical which is optionallysubstituted one or more times by halogen, alkoxy, hydroxyl,dialkylamino, cycloalkylamino, acylamino, acyl, nitro, alkylthio,alkylsulphinyl, alkylsulphonyl, nitrile, carbalkoxy or carbamoylradicals or by cycloalkyl radicals optionally substituted by alkyl,alkoxy or carbalkoxy, or by cycloalkenyl radicals, which can optionallybe bridged, or by an aliphatic or aromatic heterocyclic radical, byaryl, aryloxy, arylthio, acyloxy, alkoxycarbonylamino or ureido groups,or R' is a cycloalkyl or cycloalkenyl radical containing 3 to 10 carbonatoms which is optionally substituted by alkyl, alkoxy, alkoxycarbonylor oxo groups and is also optionally interrupted by hetero atoms andoptionally bridged by 1 to 3 carbon atoms, or R' is an aryl or hetarylradical, the aryl and hetaryl radicals being optionally substituted byhalogen, alkoxy, alkyl, hydroxyl, carbalkoxy, carbamoyl, dialkylamino,cycloalkylamino, acylamino, nitro, cyano, acyl, alkylthio,alkylsulphinyl, alkylsulphonyl, sulphamoyl, phenyl, trifluoromethyl,aryloxy, acyloxy or methylenedioxy; and R₁ is a hydrogen atom or asaturated, straight-chained or branched alkyl radical containing up to 4carbon atoms or a phenyl radical, with the proviso that when X is acyano group or an alkoxycarbonyl radical and R₁ is a hydrogen atom, R'is not an unsubstituted alkyl radical or an alkyl radical substituted byhydroxyl, alkoxy, dialkylamino, phenyl, 4-chlorophenyl or4-methoxyphenyl or a vinyl radical substituted by a phenyl or methylradical, or a cycloalkyl radical, a phenyl, a 4-chlorophenyl, a4-methoxyphenyl, an s-triazinyl or a pyridinyl radical and with theproviso that when X is a carbamoyl group and R₁ is a hydrogen atom, R'is not an unsubstituted cyclohexyl, alkyl or benzyl radical and with theproviso that when X is a cyano group or an alkoxycarbonyl radical and R₁is a phenyl radical, R' is not an isopropyl, cyclohexyl, phenyl, benzylor p-chlorobenzyl radical and when R₁ is a methyl radical, is not abenzyl, p-chloro- or p-methoxybenzyl radical.

Preferred new compounds of general formula I' according to the presentinvention include:

2-Cyano-1-(2-methylsulphinylethyl)-aziridine

2-Cyano-1-(2-cyanoethyl)-aziridine

1-(3-Chloropropyl)-2-cyanoaziridine

1-(2-Acetamidoethyl)-2-cyanoaziridine

1-(2-Benzamidoethyl)-2-cyanoaziridine

2-Cyano-1-(2-carbamoylethyl)-aziridine

2-Cyano-1-(but-2-ynyl)-aziridine

2-Cyano-1-(4-hydroxy-3-methoxyphenyl)-aziridine

2-Cyano-1-(cyclohept-2-enylmethyl)-aziridine

2-Cyano-1-(cyclohept-3-enyl)-aziridine

1-(1-Acetylpiperidin-4-yl)-2-cyanoaziridine

2-Cyano-1-(thian-3-yl)-aziridine

2-Cyano-1-(2,2,2-trichloroethyl)-aziridine

2-Cyano-1-(3,4-methylenedioxybenzyl)-aziridine

2-Cyano-1-(2,2,2-trifluoroethyl)-aziridine

2-Cyano-1-(2-nitroethyl)-aziridine

2-Cyano-1-(1-naphthylmethyl)-aziridine

1-Benzyl-aziridine-2-carboxylic acid

1-Allyl-2-cyano-3-phenyl-aziridine

2-Cyano-1-(pent-3-enyl)-aziridine

2-Cyano-1-(4-cyanobenzyl)-aziridine

2-Cyano-1-(2-methylcyclohexyl)-aziridine

2-Cyano-1-(4-methoxycyclohexyl)-aziridine

2-Cyano-1-(pyrimidin-2-yl)-aziridine

2-Cyano-1-(4-phenylbenzyl)-aziridine

2-Cyano-1-(2-methylsulphinylbenzyl)-aziridine

2-Cyano-1-(2-methylsulphonylbenzyl)-aziridine

2-Cyano-1-(4-sulphamoylbenzyl)-aziridine

2-Cyano-1-(3-carbamoylbenzyl)-aziridine

1-(4-Acetylbenzyl)-2-cyanoaziridine

1-(2-Acetamido-5-methylbenzyl)-2-cyanoaziridine

2-Cyano-1-(3,4,5-trimethoxybenzyl)-aziridine

2-Cyano-1-(naphth-1-yl)-aziridine

2-Cyano-1-(thiazol-2-yl)-aziridine

Methyl 2-cyano-1-aziridine-propionate

1-Allyl-2-cyanoaziridine

2-Cyano-1-(3-morpholinopropyl)-aziridine

2-Cyano-1-(2-pyrrolidinoethyl)-aziridine

2-Cyano-1-[3-(2-methylpiperidino)-propyl]-aziridine

2-Cyano-1-(2-α-furoylaminoethyl)-aziridine

2-Cyano-1-(4-methylsulphonamidobenzyl)-aziridine

2-Cyano-1-(4-phenoxybenzyl)-aziridine

Ethyl 3-(2-cyanoaziridin-1-yl)-propionate

2-Cyano-1-(4-hydroxybenzyl)-aziridine

2-Cyano-1-(cyclohex-1-enylmethyl)-aziridine

2-Cyano-1-(2-thenyl)-aziridine

2-Cyano-1-(2-furylmethyl)-aziridine

2-Cyano-1-(2-methylallyl)-aziridine

1-(1-Adamantyl)-2-cyanoaziridine

Ethyl 2-cyano-1-aziridine-acetate

3-(2-Cyano-aziridin-1-yl)-acrolein

Dimethyl 3-(2-cyanoaziridin-1-yl)-fumarate

Ethyl 3-(2-cyanoaziridin--yl)-acrylate

1-Phenyl-1-(2-cyanoaziridin-1-yl)-2-cyanoethylene

1-(2-Carbamoylaziridin-1-yl)-1-(p-methoxycarbonylphenyl)ethylene

1-Phenyl-1-(2-carbamoylaziridin-1-yl)-ethylene

1-Phenyl-1-(2-carbamoylaziridin-1-yl)-2-cyanoethylene

1-(2-Carbamoylaziridin-1-yl)-2-carbethoxy-2-cyanoethylene

4-(2-Carbamoylaziridin-1-yl)-1-methyl-3,4-dehydropiperidine

1-Allyl-2-cyano-3-methylaziridine

Ethyl 1-allylaziridine-2-carboxylate

2-Cyano-1-(2-methylthiobenzyl)-aziridine

2-Cyano-1-(3,4-dimethoxybenzyl)-aziridine

2-Cyano-1-(4-methylbenzyl)-aziridine

1-(2-Cyanoaziridin-1-yl)-2-carbethoxy-cyclohex-1-ene;

and the pharmacologically-acceptable salts thereof, as well as all thestereoisomeric forms of these compounds.

The compounds of general formula (I') can be prepared in known mannerand preferably by one of the following methods:

(a) reaction of a compound of the general formula: ##STR4## wherein R₁and X have the same meanings as above, Hal₁ and Hal₂ are chlorine orbromine atoms, L is a hydrogen atom or Hal₁ and L can together representa valency bond, with an amine of the general formula:

    R--NH.sub.2                                                (III),

wherein R has the same meaning as above; or

(b) treatment of a compound of the general formula: ##STR5## wherein X,R₁ and R have the same meanings as above and M is a chlorine or bromineatom or an A--Z grouping, A being an oxygen or sulphur atom and Z beinga hydrogen atom or a grouping which, together with oxygen or sulphur, iseasily eliminated, or of a salt thereof, with a reagent which splits offM--H; or

(c) reaction of a compound of the general formula: ##STR6## wherein R₁and X have the same meanings as above, with a compound of the generalformula:

    R--Y                                                       (VI)

wherein R has the same meaning as above and Y is Hal or an --O--SO₂ --ORradical, Hal being a chlorine, bromine or iodine atom; or

(d) reaction of an azide of the general formula:

    R--N.sub.3                                                 (VII),

wherein R has the same meaning as above, with a compound of the generalformula:

    R.sub.1 --CH═CH--X                                     (VIII)

wherein R₁ and X have the same meanings as above, to give a compound ofgeneral formula (I), whereby, as intermediate, there can be formed atriazoline of the general formula: ##STR7## wherein R, R₁ and X have thesame meanings as above, which, by thermolysis or photolysis, can beconverted, with the splitting of nitrogen, into a compound of generalformula (I); or

(e) reaction of an epoxide of the general formula: ##STR8## wherein R₁and X have the same meanings as above, with an amine of general formula(III); or

(f) reaction of a compound of the general formula (V) with a compound ofthe general formula:

    T--C.tbd.C--U                                              (XI),

wherein T is a hydrogen atom or an alkyl or carboxylic acid ester groupand U is an aldehyde or carboxylic acid ester group; or

(g) reaction of a compound of the general formula (V) with a compound ofthe general formula: ##STR9## wherein B is an optionally substitutedalkyl or phenyl radical, D is an optionally substituted alkyl radical orB and D together can represent a ring which is optionally interrupted byhetero atoms; or

(h) subjection of an oxazolidinone of the general formula: ##STR10##wherein R, R₁ and X have the same meanings as above, to thermolysis; or

(i) treatment of a compound of the general formula: ##STR11## wherein R,R₁ and X have the same meanings as above and G is a hydrogen atom or Haland E is Hal or a trialkylamino or arylsulphonic acid ester radical, Halbeing a chlorine or bromine atom, with a reagent splitting off E--G;whereafter, if desired, a compound obtained of general formula (I) cansubsequently be converted into another compound of general formula (I)and, if desired, a compound obtained of general formula (I) can beconverted into a pharmacologically-acceptable salt.

Process (a) for the preparation of aziridine derivatives of generalformula (I) is known from the literature (see, for example, Gundermannet al., Chem. Ber., 105, 312/1972; and Wagner-Jauregg, Helv. Chim. Acta,44, 1237/1961). It is preferable to use an inert solvent, for example,diethyl ether, dioxane, hexane, toluene or the like, but it is alsopossible to use a lower alcohol, for example methanol, ethanol or thelike. The reaction temperature can be from 0° to 80° C. and ispreferably ambient temperature. The reaction period varies from 3 hoursto 10 days.

In the case of process (b), the reagent splitting off M--H is a base,especially a tertiary amine, for example, triethylamine,triethanolamine, dicyclohexylethylamine or the like. In this case, too,an inert solvent can be used, for example, diethyl ether, dioxane,benzene or toluene, but also an alcohol, for example methanol orethanol. Furthermore, in some cases, an alcoholate, for example sodiummethylate or sodium ethylate, in the corresponding alcohol, can be used.Especially when the A--Z group is a hydroxyl group, as the agent forsplitting off water, it has proved to be especially useful to usetriphenylphosphine in the presence of carbon tetrachloride andtriethylamine, in which case, as a rule, methylene chloride orchloroform is used as solvent. However, this splitting off of water canalso be carried out with sulphuric acid. In the case of process (b), thereaction time is from 3 to 24 hours.

The alkylation reaction in the case of process (c) is preferably carriedout in water, an alcohol, for example methanol or ethanol, or in analcohol/water mixture in the presence of a base. Besides organic bases,there can also be used inorganic bases, for example, alkali metalcarbonates or alkali metal bicarbonates, as acid acceptors. As a rule,the reaction is carried out at a temperature of from 20° to 60° C. Inorder to accelerate the reaction, it is also possible to add a phasetransfer catalyst, for example, triethylbenzyl ammonium chloride.

The thermolysis of the triazolines in the case of process (d) can becarried out at a temperature of from 80° to 150° C. and preferably offrom 100° to 120° C. It is possible to work without the use of a solventand to purify the resultant aziridine derivative by distillation orrecrystallization. However, it is also possible to use a solvent, aninert solvent, such as, for example, benzene, toluene and xylene, havingproved to be especially useful. As a rule, photolysis is carried out atambient temperature in solution, in which case it is especiallypreferred to use benzene, toluene or acetonitrile as solvent. Thephotolysis can be carried out with or without a sensitizer, for example,benzoquinine or acetophenone (see, for example J.A.C.S., 90, 988/1968).

In the case of process (e), an epoxide of general formula (X) can bereacted with an amine of the general formula (III) and the aminoalcoholthereby obtained dehydrated, as described in process (b), to give anaziridine derivative of general formula (I). However, for the conversionof the epoxide into an aziridine, use can also be made of compounds suchas R--N--P(O)(OAlk)₂ ⁻ or Ph₃ P═N--R, wherein R has the same meaning asabove, Ph is a phenyl radical and Alk is a lower alkyl radical, forexample a methyl or ethyl radical (see Tetrahedron Letters, 1976, 4003and Chem. Ber. 109, 814/1976).

In the case of processes (f) and (g), the reaction components are, as arule, reacted without the use of a solvent at a temperature of from 0°to 60° C. The reaction products possibly have to be purified by columnchromatography.

Oxazolidinones of general formula (XIII) are, as a rule, thermolyzedwithout the use of a solvent in the presence of a base, for example,triethanolamine or dicyclohexylethylamine, the reaction product beingremoved by distillation during the thermolysis. The thermolysistemperature can be from 170° to 250° C.

In the case of process (i), when G is a hydrogen atom, the reagent usedfor splitting off E--G is preferably an alcoholate, such as an alkalimetal methylate or alkali metal ethylate, in the corresponding alcohol.However, it is also possible to use a tertiary amine, for example,triethylamine, triethanolamine or dicyclohexylethylamine, in a solvent,for example, methanol, ethanol, benzene, toluene, diethyl ether ordioxane. When G and E are Hal, the splitting off reaction can be carriedout with the use of a conventional dehalogenation agent and preferablywith zinc or sodium.

The subsequent conversion of compounds of general formula (I) into othercompounds of general formula (I) can be carried out, on the one hand, byconversion of the substituent X. In this case, for example, a compoundin which X is an alkoxycarbonyl radical can be converted, by reactionwith ammonia, into a compound in which X is a carbamoyl group which, inturn, can be converted with a dehydration agent into a compound in whichX is a nitrile group.

Compounds of general formula (I) in which X is an alkoxycarbonyl orcarbamoyl group can, therefore, also be used as intermediates for thepreparation of compounds of general formula (I) in which X is a nitrilegroup.

The conversion of an ester group into an amide group can be carried outwith gaseous ammonia in an organic solvent, preferably in methanol orethanol, or with aqueous ammonia at a temperature of from 0° to 25° C.The desired amide either precipitates out or can be isolated from thereaction mixture by, for example, column chromatography.

A carbamoyl group can be converted into a nitrile group by using adehydration agent known from the literature and preferably with amixture of triphenylphosphine, carbon tetrachloride and triethylamine.The solvent usually employed is a halogenated hydrocarbon, for examplemethylene chloride or chloroform, but acetonitrile can also be used. Asa rule, the desired nitrile is isolated from the reaction mixture bydistillation.

The 2-alkoxycarbonyl-, 2-carbamoyl- and 2-cyanoaziridine derivatives areusually converted into 2-carboxyaziridines by saponification processeswhich are known from the literature.

For the production of pharmaceutical compositions withimmune-stimulating action, the compounds of general formula (I) aremixed in conventional manner with appropriate pharmaceutical carriermaterials, optionally granulated and pressed, for example, into tabletsor dragee cores. The mixture can also be filled into hard gelatinecapsules. With the addition of appropriate adjuvants, there can also beproduced a solution or suspension in water, an oil, for example oliveoil, or high molecular weight polymer, for example polyethylene glycol,which can then be worked up to give injection solutions, soft gelatinecapsules, syrups or drops.

Since the active materials are acid labile, the compositions are eitherprovided with a coating which only dissolves in the alkaline medium ofthe small intestine or an adjuvant, such as antacid, for examplemagnesium oxide, which is able to neutralize the gastric juices to a pHvalue above 6, is incorporated into the formulation.

Examples of solid carrier materials which can be used include starch,starch derivatives, sugar, sugar alcohols, celluloses and cellulosederivatives, tensides, talc, highly-dispersed silicic acids, highmolecular weight fatty acids and the salts thereof, gelatine, agaragar,calcium phosphate, animal and vegetable fats and waxes and solid highmolecular weight polymers, for example polyethylene glycols orpolyvinylpyrrolidones. If liquid active materials are to be worked up togive tablets or hard gelatine capsules, in addition to highly-dispersedsilicic acid, there can also be used carriers, such as phosphates,carbonates and oxides. Compositions suitable for oral administrationcan, if desired, contain flavoring and/or sweetening agents.

For pharmaceutical combinations in which compounds of general formula(I) are present together with a chemotherapeutic agent, in general thereare used the same galenical forms of composition as are described abovefor the individual substances. The two active materials, i.e. the immunestimulant and the chemotherapeutic agent, are usually present in thecomposition in a weight ratio of 10:1 to 1:10, it having proved to beadvantageous to use an equimolar ratio of the two components.

A preferred composition comprises 100 mg. of chloramphenicol aschemotherapeutic agent and 33.3 mg. of 1-allyl-2-cyanoaziridine,together with appropriate carrier materials, such as starch, and can beproduced in the form of a 250 mg. tablet which, as a rule, are takenorally twice a day.

For the demonstration of the immune-stimulating action, there isemployed, as already mentioned, on the one hand the influencing of anacute infection with Escherichia coli (108) in mice by an immunestimulant selected from compounds of general formula (I), for example1-allyl-2-cyanoaziridine (B), with the simultaneous administration of asubtherapeutic dose of chloramphenicol (A).

Experimental Protocoll

Groups of 20 female adult NMRI mice (body weight 25 to 30 g.) were, on 0day, infected with 1.0×10⁷ micro-organisms/animal (Escherichia coli)intraperitoneally. Treatment was carried out as follows:

1st Group: 40 mg./kg. A, oral, dissolved in 0.5% tylose solution

2nd Group: 13.4 mg./kg. B, oral, dissolved in 0.5% tylose solution

3rd Group: 40 mg./kg. A+13.4 mg./kg. B, oral, dissolved in 0.5% tylosesolution

4th Group: 10 mg./kg. A, oral, dissolved in 0.5% tylose solution

5th Group: 3.3 mg./kg. B, oral, dissolved in 0.5% tylose solution

6th Group: 10 mg./kg. A+3.3 mg./kg. B, oral, dissolved in 0.5% tylosesolution

7th Group: control: tylose solution.

Results:

    ______________________________________                                        % Survival                                                                           A       B       1st  2nd  3rd  4th  5th  6th                           GROUP  mg/kg.  mg/kg.  day  day  day  day  day  day                           ______________________________________                                        1      40          --    70   70   65   65   65   65                          2      --          13.4  0    0    0    0    0    0                           3      40    +     13.4  100  100  100  100  100  100                         4      10          --    15   15   15   15   15   15                          5      --           3.3  10   10   10   10   10   10                          6      10    +      3.3  65   55   50   50   50   50                          Control                                                                              0            0    0    0    0    0    0    0                           ______________________________________                                    

On the other hand, in a leukocyte screening test, the increase of theleukocytes after oral administration of compounds of general formula (I)was determined.

Experimental Protocoll

Groups of 10 female, adult Sprague-Dawley rats were fasted and thenblood was sampled from the retro-orbital=venous complex and theleukocytes counted with the help of a Coulter counter. Subsequently, thecompounds to be investigated were administered orally in a dosage of 200mg./kg., dissolved or suspended in 0.5% tylose solution. 4 days later,again after fasting overnight, blood was taken from the retro-orbitalvenous complex and the leukocytes counted in a Coulter counter and theaverage values, with standard deviations from the average value, werecalculated.

Results:

    ______________________________________                                        Substance    0 day   4th day      Example                                     ______________________________________                                        B            8.5     17.1          1                                          C            8.93    12.84         1(a)                                       D            8.0     13.5          1(b)                                       E            8.0     14.3          1(f)                                       F            6.7     16.2          5                                          G            7.55    10.4          5(b)                                       H            7.37    8.5           7(b)                                       I            6.5     11.2          1(c)                                       J            6.5     9.6           1(n)                                       K            8.9     12.0          1(p)                                       L            7.1     11.3         11(f)                                       M            7.1     12.3         13(o)                                       N            7.4     11.3         16(a)                                       O            7.0     13.7         13(a)                                       P            6.6     10.6         13(c)                                       Q            6.3     11.9         13(d)                                       R            7.9     12.3         13(x)                                       S            7.5     13.5         13(v)                                       T            7.0     13.2         13(e)                                       U            8.0     11.9          6(b)                                       V            7.8     11.9          6(c)                                       W            6.9     10.6          6(d)                                       X            5.8     11.9         13(w)                                       Z            6.7     9.8          13(i)                                       ______________________________________                                         A = Chloramphenicol                                                           B = 1Allyl-2-cyanoaziridine                                                   C = 2Cyano-1-methylaziridine                                                  D = 2Cyano-1-n-propylaziridine                                                E = 1Benzyl-2-cyanoaziridine                                                  F = 3(2-Cyanoaziridin-1-yl)-acrolein                                          G = Ethyl 3(2-Cyanoaziridin-1-yl)-acrylate                                    H = 1Phenyl-1-(2-carbamoylaziridin-1-yl)-2-cyanoethylene.                     I = 2Cyano-1-isopropylaziridine                                               J = 2Cyano-1-(2-thenyl)-aziridine                                             K = 2Cyano-2-(2-methylallyl)-aziridine                                        L = 1(2-Chloroethyl)-2-cyanoaziridine                                         M = 2Cyano-1-(3-trifluoromethylbenzyl)-aziridine                              N = 2Cyano-1-(5-carboxy-2-furfuryl)-aziridine                                 O = 2Cyano-1-(5-methoxycarbonyl-2-thenyl)-aziridine                           P = 2Cyano-1-(2,2-dichloroethyl)-aziridine                                    Q = 1(But-2-enyl)-2-cyanoaziridine                                            R = 2Cyano-1-(5-methyl-2-nitrobenzyl)-aziridine                               S = 1(2-Chlorobenzyl)-2-cyanoaziridine                                        T = 2Cyano-1-(5-methylpyrimidin-4-ylmethyl)-aziridine                         U = L(-)2-Cyano-(L-(-)phenylethyl)-aziridine                                  V = D(+)2-Cyano-1-(L-(-)phenylethyl)-aziridine                                W = L(-)2-Cyano-1-(D-(+)phenylethyl)-aziridine                                X = 2Cyano-1-(pyrimidin-2-ylmethyl)-aziridine                                 Z = 2Cyano-1-[(2methoxy-6-methylpyridin-3-yl)-methylaziridine.           

2-Cyanoaziridines wherein the nitrogen is substituted by alkyl radicalsshow only insignificant secondary effects. Thus in opposition to knownaziridines the compounds of the invention possess no or only smallmutagenic effects proved in the Ames-Test.

Apart from the compounds mentioned in the following examples, preferredcompounds according to the present invention for the preparation ofpharmaceutical compositions with immune-stimulating action include thefollowing compounds:

2-Cyano-1-(2-dimethylaminoethyl)-aziridine

2-Cyano-1-(2-methylsulphinylethyl)-aziridine

2-Cyano-1-(2-cyanoethyl)-aziridine

1-(3-Chloropropyl)-2-cyanoaziridine

1-(2-Acetamidoethyl)-2-cyanoaziridine

1-(2-Benzamidoethyl)-2-cyanoaziridine

2-Cyano-1-(2-carbamoylethyl)-aziridine

2-Cyano-1-(prop-1-enyl)-aziridine

2-Cyano-1-(but-2-ynyl)-aziridine

2-Cyano-1-(4-hydroxy-3-methoxybenzyl)-aziridine

2-Cyano-1-(cyclohept-2-enylmethyl)-aziridine

2-Cyano-1-(cyclohept-3-enyl)-aziridine

1-(1-Acetylpiperidin-4-yl)-2-cyanoaziridine

2-Cyano-1-(thian-3-yl)-aziridine

2-Cyano-1-(2,2,2-trichloroethyl)-aziridine

2-Cyano-1-(3,4-methylenedioxybenzyl)-aziridine

2-Cyano-1-(2,2,2-trifluoroethyl)-aziridine

2-Cyano-1-(2-nitroethyl)-aziridine

2-Cyano-1-(1-naphthylmethyl)-aziridine

1-Benzyl-aziridin-2-carboxylic acid

1-Allyl-2-cyano-3-phenyl-aziridine

2-Cyano-1-(pent-3-enyl)-aziridine

2-Cyano-1-(4-cyanobenzyl)-aziridine

2-Cyano-1-(2-methylcyclohexyl)-aziridine

2-Cyano-1-(4-methoxycyclohexyl)-aziridine

2-Cyano-1-(pyrimidin-2-yl)-aziridine

2-Cyano-1-(4-phenylbenzyl)-aziridine

2-Cyano-1-(2-methylsulphinyl-benzyl)-aziridine

2-Cyano-1-(2-methylsulphonyl-benzyl)-aziridine

2-Cyano-1-(4-sulphamoylbenzyl)-aziridine

2-Cyano-1-(3-carbamoylbenzyl)-aziridine

1-(4-Acetylbenzyl)-2-cyanoaziridine

1-(2-Acetamido-5-methylbenzyl)-2-cyanoaziridine

2-Cyano-1-(3,4,5-trimethoxybenzyl)-aziridine

2-Cyano-1-(naphth-1-yl)-aziridine

2-Cyano-1-(thiazol-2-yl)-aziridine

Methyl S-2-[(-)-2-cyano-1-aziridine]-propionate

Methyl R-2-[(+)-2-cyano-1-aziridine]-propionate

(+)-1-Allyl-2-cyanoaziridine

(-)-1-Allyl-2-cyanoaziridine

2-Cyano-1-(3-morpholinopropyl)-aziridine

2-Cyano-1-(2-pyrrolidinoethyl)-aziridine

2-Cyano-1-[3-(2-methylpiperidino)-propyl]-aziridine

2-Cyano-1-(2-α-furoylaminoethyl)-aziridine

2-Cyano-1-(4-methylsulphonamidobenzyl)-aziridine

2-Cyano-1-(4-phenoxybenzyl)-aziridine.

The following examples, which are given for the purpose of illustratingthe present invention, show some of numerous process variants which canbe used for the synthesis of the compounds according to the presentinvention. The structures of all of the compounds described in thefollowing examples have been confirmed by micro-combustion analyses, NMRspectra and mass spectra:

EXAMPLE 1 1-Allyl-2-cyanoaziridine

A solution of 28.5 g. allylamine and 51 g. triethylamine in 250 ml.toluene is added dropwise, with stirring, at 0° C. to a solution of 66g. 2-bromoacrylonitrile in 250 ml. toluene. The reaction mixture issubsequently stirred for 3 days at ambient temperature and then filteredwith suction. The filtrate is evaporated and the residue is taken up indiethyl ether, extracted once with ice-cold, dilute hydrochloric acidand washed neutral with ice water. This solution is then passed over 400g. of deactivated aluminum oxide. After evaporation, the residue isdistilled twice. There are obtained 28.6 g. (about 53% of theory)1-allyl-2-cyanoaziridine; b.p.₀.2 : 53°-55° C.

In an analogous manner, by the reaction of 2-bromoacrylonitrile with theappropriate amines, there are obtained the following compounds, whichare known from the literature:

(a) 2-cyano-1-methylaziridine (b.p.₁₁ : 53°-54° C.)

(b) 2-cyano-1-n-propylaziridine (b.p.₁₅ : 80°-82° C.)

(c) 2-cyano-1-isopropylaziridine (b.p.₁₅ : 53°-55° C.)

(d) 2-cyano-1-n-pentylaziridine (b.p.₀.3 : 50°-52° C.)

(e) 1,6-bis-(2-cyanoaziridin-1-yl)-hexane (m.p.: 64°-66° C.)

(f) 1-benzyl-2-cyanoaziridine (b.p.₀.05 : 103°-105° C.)

(g) 2-cyano-1-cyclohexylaziridine (b.p.₀.1 : 93°-94° C.)

Compounds (a) to (f) have been described by Gundermann et al. (Chem.Ber., 105, 312/1972) and compound (g) has been described byWagner-Jauregg (Helv. Chim. Acta, 44, 1237/1961).

In an analogous manner, by the reaction of 2-bromoacrylonitrile with theappropriate amines and subsequent purification by means of a silica geland/or deactivated aluminum oxide column, there are obtained thefollowing compounds:

(h) 2-Cyano-1-(2-hydroxyethyl)-aziridine

oily product; yield: 31.1% of theory

(i) Ethyl 3-(2-cyanoaziridin-1-yl)-propionate

b.p.₀.15 : 105° C.; yield: 33% of theory

(dioxane used as solvent)

(k) 2-Cyano-1-(4-hydroxybenzyl)-aziridine

m.p.: 112°-114° C.; yield: 37% of theory

(ethanol used as solvent)

(l) Methyl S-2-[(+)-2-cyano-1-aziridine]-propionate

m.p. 88°-91° C. recrystallized from diisopropyl ether;

[α]_(D) ²⁰ =+99.4° c=1 (methanol)

(m) 2-Cyano-1-(cyclohex-1-enylmethyl)-aziridine

b.p.₀.01 : 103°-105° C.; yield: 42.9% of theory

(n) 2-Cyano-1-(2-thenyl)-aziridine

b.p.₀.1 : 90°-92° C.; yield: 20% of theory

(reaction time 10 days)

(o) 2-Cyano-1-(2-furylmethyl)-aziridine

b.p.₀.1 : 100°-101° C.; yield: 8.1% of theory

(reaction time 10 days)

(p) 2-Cyano-1-(2-methylallyl)-aziridine

b.p.₀.1 : 36°-38° C.; yield: 16.4% of theory

(q) 1-(1-Adamantyl)-2-cyanoaziridine

m.p. 62°-64° C.; yield: 51.8% of theory

(dioxane used as solvent).

EXAMPLE 2 1-tert.-Butyl-2-cyanoaziridine

6.0 g. 2-Bromo-3-tert-butylaminopropionitrile hydrobromide (prepared byreacting 2,3-dibromopropionitrile with tert.-butylamine; m.p. 188°-190°C.) are dissolved in 50 ml. methanol and heated under reflux for 4 hourswith 25 ml. triethanolamine. The solution is then evaporated,neutralized with 2 N sulphuric acid and extracted with diethyl ether andthe collected ethereal fractions are dried and evaporated, the residueobtained being subsequently distilled. There is obtained 1.2 g. (about39.5% of theory) 1-tert.-butyl-2-cyanoaziridine; b.p.₀.2 : 52°-54° C.;m.p. 53°-54° C.

The following compounds are obtained in an analogous manner:

(a) reaction of 2-bromo-3-n-pentylaminopropionitrile hydrochloride(prepared by reacting 2,3-dibromopropionitrile with n-pentylamine; m.p.133°-135° C.) with triethanolamine gives 2-cyano-n-pentylaziridine;b.p.₀.3 : 50°-52° C.; yield 43% of theory;

(b) reaction of 2-bromo-3-(carbethoxymethylamino)-propionitrilehydrochloride (prepared by reacting 2,3-dibromopropionitrile withglycine ethyl ester; m.p. 70°-75° C.) with triethanolamine gives ethyl2-cyano-1-aziridine-acetate; b.p.₀.1 : 88°-90° C.; yield 34% of theory;

(c) reaction of 2-bromo-3-[(1-carbomethoxyethyl)-amino]-propionitrile(prepared by reacting 2,3-dibromopropionitrile with L-alanine methylester; oily substance) with triethylamine gives methylS-2-[(+)-2-cyano-1-aziridine]-propionate; m.p. 88°-91° C.(recrystallized from diisopropyl ether); [α]_(D) ²⁰ =+99.4° (c=1 inmethanol).

EXAMPLE 3 1-Allyl-2-cyanoaziridine

4.2 g. Sodium bicarbonate are dissolved in 30 ml. ethanol/15 ml. water,3.4 g. 2-cyanoaziridine are added thereto and 8.4 g. freshly distilledallyl iodide are added dropwise, whereafter the reaction mixture isstirred for 72 hours at ambient temperature. The solution is thenevaporated on a rotary evaporator and the residue is taken up in waterand extracted several times with diethyl ether. After drying, thediethyl ether is stripped off and the residue separated with the use ofa silica gel column (elution agent: diethyl ether/ligroin 2:1 v/v). Thecrude 1-allyl-2-cyanoaziridine thus obtained is subsequently distilled.The yield is 1.24 g. (23% of theory) b.p.₀.2 : 53°-55° C.

EXAMPLE 4 2-Cyano-1-phenylaziridine

A mixture of 11.65 g. phenyl azide and 18 g. acrylonitrile is left tostand in the dark for 9 days at ambient temperature. Excessacrylonitrile is then stripped off in a vacuum and the4-cyano-1-phenyltriazoline-(2) obtained as an intermediate (a samplethereof was crystallized with cyclohexane; m.p. 87°-91° C.) is dissolvedin 80 ml. toluene and heated to 100° C. for 40 minutes, nitrogen therebybeing evolved. The toluene is stripped off in a vacuum and the residuedistilled. There are obtained 5.9 g. (42% of theory)2-cyano-1-phenylaziridine; b.p.₀.1 : 109°-111° C.

EXAMPLE 5 3-(2-Cyanoaziridin-1-yl)-acrolein

5.78 g. 2-Cyanoaziridine are added dropwise, with cooling, to 4.6 g.propargyl aldehyde. The reaction mixture is stirred overnight at 20° C.,the dark oil obtained is taken up in 500 ml. ethanol and the solution istreated with active charcoal, filtered and concentrated to 50 ml. Uponcooling with ice, the desired product precipitates out and is washedwith ethanol/diethyl ether. There are obtained 4.2 g. (41% of theory)3-(2-cyano-aziridin-1-yl)-acrolein; m.p. 57°-58° C.

The following compounds are obtained in an analogous manner by reacting2-cyanoaziridine with:

(a) dimethyl acetylene-dicarboxylate:

dimethyl 3-(2-cyanoaziridin-1-yl)-fumarate; m.p. 127°-128° C.(recrystallized from ethanol); yield 11% of theory;

(b) ethyl propiolate:

ethyl 3-(2-cyanoaziridin-1-yl)-acrylate; oily substance, purified with asilica gel column; yield 24% of theory.

EXAMPLE 6 1-Phenyl-1-(2-cyanoaziridin-1-yl)-2-cyanoethylene

2.7 g. 1-Phenyl-1-(2-carbamoylaziridin-1-yl)-2-cyanoethylene and 5.0 g.triphenyl phosphine are dissolved in a mixture of 400 ml. anhydrousmethylene chloride, 1.76 g. triethylamine and 1.2 ml. anhydrous carbontetrachloride and the reaction mixture then stirred under reflux, thedehydration reaction being monitored by thin layer chromatography. Thereaction mixture is then evaporated and the residue purified on a silicagel column with the elution mixture chloroform/acetone/cyclohexane(5:5:1 v/v/v). The desired fraction is caused to crystallize withligroin. There is obtained 0.7 g. (23.5% of theory)1-phenyl-1-(2-cyanoaziridin-1-yl)-2-cyanoethylene; m.p. 95° C.(recrystallized from diethyl ether).

The following compounds are obtained in an analogous manner from theindicated starting materials:

(a) 1-(2-Carbamoylaziridin-1-yl)-2-carbethoxy-cyclohex-1-ene

1-(2-Cyanoaziridin-1-yl)-2-carbethoxy-cyclohex-1-ene

m.p.: 101°-104° C.; yield: 54.5% of theory

(b) L-(-)-1-(L-(-)-Phenylethyl)-aziridine-2-carboxamide

(see Example 14)

L-(-)-2-Cyano-(L-(-)-phenylethyl)-aziridine

m.p.: 44°-48° C.; yield: 45% of theory

[α]_(D) ²⁰ : -129.4° (c=1 in methanol)

(c) D-(+)-1-(L-(-)-Phenylethyl)-aziridine-2-carboxamide

(see Example 14a)

D-(+)-2-Cyano 1-(L-(-)-phenylethyl)-aziridine

oily substance; yield: 51% of theory

[α]_(D) ²⁰ : +58.8° (c=1 in methanol)

(d) L-(-)-1-(D-(+)-Phenylethyl)-aziridine-2-carboxamide

(see Example 14b)

L-(-)-2-Cyano-1-(D-(+)-phenylethyl)-aziridine

oily substance; yield: 74% of theory

[α]_(D) ²⁰ : -53.5° (c=1 in methanol)

(e) D-(+)-1-(D-(+)-Phenylethyl)-aziridine-2-carboxamide

(see Example 14c)

D-(+)-2-Cyano-1-(D-(+)-phenylethyl)-aziridine

m.p. 45°-48° C.; yield: 62% of theory

[α]_(D) ²⁰ : +128.1° (c=1 in methanol)

EXAMPLE 71-(2-Carbamoylaziridin-1-yl)-1-(p-methoxycarbonylphenyl)-ethylene

2.7 g. p-Methoxycarbonylacetophenone and 1.03 g. 2-cyanoaziridine aremixed and, after the addition of 1.05 ml. triethylamine, stirred for 3hours at 60° C. After cooling, the reaction mixture is stirred withdiethyl ether. The residue is brought to crystallization with a mixtureof chloroform and methanol (9:1 v/v). There is obtained 0.9 g. (24% oftheory)1-(2-carbamoylaziridin-1-yl)-1-(p-methoxycarbonylphenyl)-ethylene; m.p.140°-141° C. (decomp.).

The following compounds are obtained in an analogous manner by reacting2-cyanoaziridine with

(a) acetophenone:

1-phenyl-1-(2-carbamoylaziridin-1-yl)-ethylene; m.p. 93°-96° C.; yield16% of theory

(b) α-cyanoacetophenone:

1-phenyl-1-(2-carbamoylaziridin-1-yl)-2-cyanoethylene; m.p. 164°-167° C.(recrystallized from ethyl acetate); yield 84.5% of theory

(c) ethyl cyclohexanone-2-carboxylate:

1-(2-carbamoylaziridin-1-yl)-2-carboethoxycyclohex-1-ene; m.p. 168°-170°C.; yield 17% of theory (reaction time 70 hours; crystallized bytrituration with ethyl acetate)

(d) 1-methylpiperidinone-(4):

4-(2-carbamoylaziridin-1-yl)-1-methyl-3,4-dehydropiperidine; m.p.149°-150° C.; yield 12% of theory (reaction time 24 hours, crystallizedby trituration with isopropanol).

EXAMPLE 8 1-Allyl-2-cyano-3-methylaziridine

13.4 g. Crotonitrile are mixed at ambient temperature, within the courseof 2 hours, with 32 g. bromine and the solution then heated to 30° C.until decolorized. The reaction mixture is diluted with 100 ml. diethylether and cooled to 0° C. A solution of 20.2 g. triethylamine in 50 ml.diethyl ether is added dropwise thereto and the reaction mixture furtherstirred for 1 hour at 0° C. To the suspension obtained is added at 0° C.a mixture of 20.2 g. triethylamine and 11.4 g. allylamine in 100 ml.diethyl ether and the reaction mixture stirred for 4 days at ambienttemperature. The precipitate obtained is filtered off with suction,washed with diethyl ether and the ethereal solution, after drying,passed over 250 g. deactivated aluminum oxide. The eluate issubsequently evaporated and fractionated. There are obtained 10.3 g.(42.2% of theory) 1-allyl-2-cyano-3-methylaziridine; b.p.₀.1 : 55°-57°C.

EXAMPLE 9 Ethyl 1-benzylaziridine-2-carboxylate

55.3 ml. Triethylamine are added, with stirring, at 0° C. to 52 g. ethyl2,3-dibromopropionate in 250 ml. toluene and, after 2 hours, a solutionof 21.4 g. benzylamine in 250 ml. toluene added thereto. The reactionmixture is subsequently further stirred for 3 days at ambienttemperature. The suspension is then shaken out several times with waterand the organic phase is dried and evaporated and the residue is takenup in diethyl ether. The ethereal solution is passed over 400 g.deactivated aluminum oxide and the eluate is evaporated andfractionated. There are obtained 30.7 g. (about 75% of theory) ethyl1-benzylaziridine-2-carboxylate; b.p.₀.03 : 98°-101° C.

The following compounds are obtained in an analogous manner by reactingethyl 2,3-dibromopropionate with:

(a) methylamine:

ethyl 1-methylaziridine-2-carboxylate; b.p.₁₈ : 70°-72° C.; yield 40% oftheory

(b) allylamine:

ethyl 1-allylaziridine-2-carboxylate; b.p.₁₂ : 91°-92° C.; yield 24% oftheory.

EXAMPLE 10 2-Cyano-1-methylaziridine

5.0 g. 1-(2-Cyanoethyl)-1-methyl-2,2,2-trimethylhydrazinium iodide (m.p.125°-130° C.) are heated to 40° C. for 12 hours in a solution of 0.2 g.sodium methylate in 30 ml. methanol, trimethylamine being liberatedduring the reaction. Subsequently, the reaction mixture is evaporated,the residue is passed over a silica gel column (elution agent:acetone/toluene 1:1 v/v) and the crude product so obtained is distilledtwice. There is obtained 0.35 g. (about 23% of theory)2-cyano-1-methylaziridine; b.p.₁₁ : 53°-54° C.

EXAMPLE 11

In a manner analogous to that described in Example 1, the followingcompounds are obtained by reacting 2-bromoacrylonitrile with:

(a) 2-methylthiobenzylamine:

2-cyano-1-(2-methylthiobenzyl)-aziridine; oily product; yield 54% oftheory

(b) 3,4-dimethoxybenzylamine:

2-cyano-1-(3,4-dimethoxybenzyl)-aziridine; oily product; yield 25% oftheory

(c) 4-methylbenzylamine:

2-cyano-1-(4-methylbenzyl)-aziridine; b.p.₀.05 : 113°-115° C.; yield 23%of theory

(d) cyclopropylamine:

2-cyano-1-cyclopropylaziridine; b.p.₁.5 : 70° C.; yield 22% of theory

(e) 2-methyl-3-carbethoxybenzylamine:

2-cyano-1-(2-methyl-3-carbethoxybenzyl)-aziridine; b.p.₀.01 : 168°-170°C.; m.p. 40°-43° C.; yield 20% of theory

(f) 2-chloroethylamine hydrochloride:

1-(2-chloroethyl)-2-cyanoaziridine (using dioxane as solvent); b.p.₀.1 :74° C.; yield 5.1% of theory

(g) 4-aminotetrahydrofuran:

1-(4-tetrahydropyranyl)-2-cyanoaziridine (using dioxane as solvent);m.p. 74°-76° C.; yield 13.2% of theory

(h) 2-methoxyethylamine:

2-cyano-1-(2-methoxyethyl)-aziridine; b.p.₀.2 : 80° C.; yield 17.5% oftheory

(i) 2-phenoxyethylamine:

2-cyano-1-(2-phenoxyethyl)-aziridine; b.p.₀.05 : 115° C.; yield 38.8% oftheory.

EXAMPLE 12 1-Benzylaziridine-2-carboxamide

0.7 g. Ethyl 1-benzylaziridine-2-carboxylate is stirred for 16 hours atambient temperature with 10 ml. concentrated aqueous ammonia solution.The precipitated crystals are filtered off with suction and washed witha little water. There is obtained 0.45 g. (about 75% of theory)1-benzylaziridine-2-carboxamide; m.p. 114°-116° C.

EXAMPLE 13

Analogously to Example 1, by the reaction of 2-bromoacrylonitrile withthe indicated starting materials, there are obtained the followingcompounds:

(a) 5-Methoxycarbonyl-2-thenylamine:

2-Cyano-1-(5-methoxycarbonyl-2-thenyl)-aziridine

m.p.: 51°-54° C.; yield: 49% of theory

(b) 5-Methoxycarbonyl-2-furfurylamine:

2-Cyano-1-(5-methoxycarbonyl-2-furfuryl)-aziridine

m.p.: 86°-89° C.; yield: 46% of theory

(c) 2,2-Dichloroethylamine:

2-Cyano-1-(2,2-dichloroethyl)-aziridine

m.p.: 94°-95° C.; yield: 16% of theory

(d) But-2-enylamine:

1-(But-2-enyl)-2-cyanoaziridine

b.p.₀.1 : 60°-61° C.; yield: 70% of theory

(e) 5-Methylpyrimidin-4-ylmethylamine:

2-Cyano-1-(5-methylpyrimidin-4-ylmethyl)-aziridine

m.p.: 88°-92° C. (recrystallized from isopropanol); yield: 56% of theory

(f) 2-Hydroxy-6-methylpyridin-3-ylmethylamine:

2-Cyano-1-[(2-hydroxy-6-methylpyridin-3-yl)-methyl]aziridine

m.p.: 187°-190° C. (recrystallized from water); yield: 47% of theory

(g) Aminoacetaldehyde dimethyl acetal:

2-Cyano-1-(2,2-dimethoxy-1-ethyl)-aziridine

b.p.₀.1 : 90°-92° C.; yield: 70% of theory

(h) 1,6-Dimethyl-2-oxo-pyridin-3-ylmethylamine:

2-Cyano-1-[(1,6-dimethyl-2-oxo-pyridin-3-yl)-methyl]-aziridine

m.p.: 82°-84° C.; yield: 78% of theory

(i) 2-Methoxy-6-methylpyridin-3-ylmethylamine:

2-Cyano-1-[(2-methoxy-6-methylpyridin-3-yl)-methyl]-aziridine

m.p.: 70°-73° C. (recrystallized from isopropanol); yield: 69% of theory

(k) 2,5-Dimethyl-pyrimidin-4-ylmethylamine:

2-Cyano-1-[(2,5-dimethyl-pyrimidin-4-yl)-methyl]aziridine

m.p.: 88°-92° C. (recrystallized from isopropanol); yield: 82% of theory

(1) 4-Methylthiazol-2-ylmethylamine:

2-Cyano-1-(4-methylthiazol-2-ylmethyl)-aziridine

m.p.: 73°-75° C.; yield: 21% of theory

(m) Prop-2-ynylamine:

2-Cyano-1-(prop-2-ynyl)-aziridine

b.p.₀.1 : 48° C.; yield: 28% of theory

(n) Tetrahydrofurfurylamine:

2-Cyano-1-tetrahydrofurfuryl-aziridine

b.p.₀.1 : 95° C.; yield: 20% of theory

(o) 3-Trifluoromethyl-benzylamine:

2-Cyano-1-(3-trifluoromethylbenzyl)-aziridine

b.p.₀.15 : 92° C.; yield: 31% of theory

(p) 3-Methylthiopropylamine:

2-Cyano-1-(3-methylthiopropyl)-aziridine

b.p.₀.05 : 110° C.; yield: 18% of theory

(q) 2-Methylsulphonylethylamine:

2-Cyano-1-(2-methylsulphonylethyl)-aziridine

oily substance; yield: 47% of theory

(r) Phenethylamine:

2-Cyano-1-phenethyl-aziridine

b.p.₀.05 : 122°-124° C.; yield: 18% of theory

(s) Cinnamylamine:

1-Cinnamyl-2-cyanoaziridine

b.p.₀.05 : 138°-140° C.; yield: 13% of theory

(t) But-3-ynylamine:

1-(But-3-ynyl)-2-cyanoaziridine

b.p.₀.1 : 70°-71° C.; yield: 68% of theory

(u) 2-Norbornylamine:

2-Cyano-1-(2-norbornyl)-aziridine

b.p.₀.05 : 84°-85° C.; yield: 20% of theory

(v) 2-Chlorobenzylamine;

1-(2-Chlorobenzyl)-2-cyanoaziridine

m.p.: 55°-57° C. (recrystallized from isopropanol); yield: 36% of theory

(w) Pyrimidin-2-ylmethylamine:

2-Cyano-1-(pyrimidin-2-ylmethyl)-aziridine

m.p.: 72°-76° C. (recrystallized from isopropanol); yield: 33% of theory

(x) 5-Methyl-2-nitrobenzylamine:

2-Cyano-1-(5-methyl-2-nitrobenzyl)-aziridine

m.p.: 95°-96° C. (recrystallized from isopropanol); yield: 41% of theory

(y) R-(-)-Alanine methyl ester:

Methyl-R-(-)-2-[L-(-)-2-Cyano-1-aziridin]-propionate

m.p.: 90°-91° C. (recrystallized from isopropyl ether); yield: 12% oftheory; [α]_(D) ²⁰ : -99.1° (c=1 in methanol).

EXAMPLE 14 L-(-)-1-(L-(-)-Phenylethyl)-aziridine-2-carboxamide

5.6 g. Ethyl L-(-)-1-(L-(-)-phenylethyl)-aziridine-2-carboxylate (seeExample 15) are dissolved in 55 ml. concentrated aqueous ammoniasolution and 55 ml. ethanol and left to stand for 72 hours at ambienttemperature. The solution is then evaporated and the residue trituratedwith diethyl ether. The white precipitate is filtered off with suctionand then washed with diethyl ether. There are obtained 3.7 g. (about 79%of theory) L-(-)-1-(L-(-)-phenylethyl)-aziridine-2-carboxamide; m.p.108°-111° C.; [α]_(D) ²⁰ : -116.5° (c=1 in methanol).

The following compounds are obtained in an analogous manner from:

(a) ethyl D-(+)-1-(L-(-)-phenylethyl)-aziridine-2-carboxylate (seeExample 15):

D-(+)-1-(L-(-)-phenylethyl)-aziridine-2-carboxamide;

m.p. 95°-98° C.; yield 70% of theory; [α]_(D) ²⁰ : +40.5° (c=1 inmethanol)

(b) ethyl L-(-)-1-(D-(+)-phenylethyl)-aziridine-2-carboxylate (seeExample 15a):

L-(-)-1-(D-(+)-phenylethyl)-aziridine-2-carboxamide;

m.p. 94°-97° C.; yield 76% of theory; [α]_(D) ²⁰ : -38.8° (c=1 inmethanol)

(c) ethyl D-(+)-1-(D-(+)-phenylethyl)-aziridine-2-carboxylate (seeExample 15b):

D-(+)-1-(D-(+)-phenylethyl)-aziridine-2-carboxamide;

m.p. 102°-104° C.; yield: 77% of theory; [α]_(D) ²⁰ : +115° (c=1 inmethanol).

EXAMPLE 15 Ethyl L-(-)-1-(L-(-)-phenylethyl)-aziridine-2-carboxylate andethyl D-(+)-1-(L-(-)-phenylethyl)-aziridine-2-carboxylate

15 g. Triethanolamine in 20 ml. ethanol are added, with stirring, to 26g. ethyl 2,3-dibromopropionate in 60 ml. ethanol and, after 1 hour,there are simultaneously added a solution of 12.1 g.L-(-)-phenylethylamine in 20 ml. ethanol and a solution of 15 g.triethanolamine in 20 ml. ethanol. The suspension is stirred for 12hours at ambient temperature and filtered off with suction. The filtrateis evaporated and the residue separated over a silica gel column intothe diastereomers using, as elution agent, diethyl ether/ligroin 2:1v/v).

Yield of L,L-isomer: 39% of theory;

oily substance; [α]_(D) ²⁰ : -90° (c=1 in ethanol)

yield of D.L-isomer: 47% of theory

oily substance; [α]_(D) ²⁰ : +53.2° (c=1 in ethanol)

In an analogous manner, by the reaction of ethyl 2,3-dibromopropionatewith D-(+)-phenylethylamine, there are obtained the following compounds:

(a) ethyl L-(-)-1-(D-(+)-phenylethyl)-aziridine-2-carboxylate; oilysubstance; yield 39% of theory;

[α]_(D) ²⁰ : -57.9° (c=1 in ethanol); and

(b) ethyl D-(+)-1-(D-(+)-phenylethyl)-aziridine-2-carboxylate; oilysubstance; yield 39% of theory;

[α]_(D) ²⁰ : +89.7° (c=1 in ethanol).

EXAMPLE 16 2-Cyano-1-(5-carboxy-2-thenyl)-aziridine

95 ml. 0.1 N Aqueous sodium hydroxide solution are added dropwise, withstirring, to 2.1 g. 2-cyano-1-(5-methoxycarbonyl-2-thenyl)-aziridine(see Example 13a) in 21 ml. acetone. When no more ester can be detectedby thin layer chromatography, the reaction mixture is evaporated in avacuum, acidified with dilute hydrochloric acid and extracted with ethylacetate. The evaporation residue is crystallized with diethyl ether.There is obtained 1.2 g. (61% of theory)2-cyano-1-(5-carboxy-2-thenyl)-aziridine; m.p. 108°-111° C. The sodiumsalt melts with decomposition at 238°-243° C.

(a) In an analogous manner, from2-cyano-1-(5-methoxycarbonyl-2-furfuryl)-aziridine (see Example 13b),there is obtained 2-cyano-1-(5-carboxy-2-furfuryl)-aziridine; m.p.108°-111° C.; yield 44% of theory.

EXAMPLE 17 1-Benzyl-2-cyanoaziridine

2.74 g. 3-Benzyl-4-cyano-2-oxazolidinone (m.p. 81°-83° C.; prepared byreacting 4-cyano-2-oxazolidinone (m.p. 95°-96° C.) with benzyl bromidein the presence of sodium hydride) are heated under reflux for 3 hoursin 20 ml. o-dichlorobenzene, with the addition of 1.5 g.triethanolamine. After cooling, the reaction mixture is extracted withice-cold 1 N hydrochloric acid, washed neutral with water, dried and theorganic phase fractionated. There are obtained 0.47 g. (about 31% oftheory) 1-benzyl-2-cyanoaziridine; b.p.₀.05 : 103°-105° C.

EXAMPLE 18

The following examples are concerned with pharmaceutical compositionswhich contain compounds of general formula (I) or salts thereof.

EXAMPLE A (Tablets)

    ______________________________________                                        active material       X       mg.                                             lactose               ad 60.0 mg.                                             polyvinylpyrrolidone  2.0     mg.                                             microcrystalline      8.0     mg.                                             cellulose                                                                     sodium carboxymethyl- 4.0     mg.                                             amylopectin                                                                   silicic acid, highly  0.5     mg.                                             dispersed                                                                     talc                  5.0     mg.                                             magnesium stearate    0.5     mg.                                             end weight            80.0    mg.                                             ______________________________________                                         X = up to 40.0 mg.                                                       

For liquid active materials in dosages of up to about 40 mg.:

    ______________________________________                                        active material      X        mg.                                             silicic acid, highly ad 100.0 mg.                                             dispersed                                                                     lactose              135.0    mg.                                             polyvinylpyrrolidone 10.0     mg.                                             microcrystalline     25.0     mg.                                             cellulose                                                                     sodium carboxymethyl-                                                                              10.0     mg.                                             amylopectin                                                                   silicic acid, highly 2.0      mg.                                             dispersed                                                                     talc                 15.0     mg.                                             magnesium stearate   3.0      mg.                                             end weight           300.0    mg.                                             ______________________________________                                         X = up to 40.0 mg.                                                       

The active materials and adjuvants are mixed, optionally granulated andpressed into dragee cores using conventional machines. The dragee coresare then coated in the usual manner with a film which is resistant togastric juices but is soluble in intestinal juice (for example ananionic polymer of methacrylic acid and methyl methacrylate).

    ______________________________________                                        active material       X       mg.                                             lactose               ad 60.0 mg.                                             magnesium oxide       100.0   mg.                                             polyvinylpyrrolidone  2.0     mg.                                             microcrystalline      8.0     mg.                                             cellulose                                                                     sodium carboxymethyl- 4.0     mg.                                             amylopectin                                                                   silicic acid, highly  0.5     mg.                                             dispersed                                                                     talc                  5.0     mg.                                             magnesium stearate    0.5     mg.                                             end weight            180.0   mg.                                             ______________________________________                                         X = up to 40.0 mg.                                                       

The active material and adjuvants are mixed, optionally granulated andpressed into tablets.

EXAMPLE B (Injection Solution)

As preparations suitable for injection, which contain1-allyl-2-cyanoaziridine, there can be mentioned aqueous solution ofpolyethylene glycol 400, ethylene glycol monoethyl ether and ethanol, aswell as a solution of the active material in "Miglyol" 812 neutral oil,the latter adjuvant only being used for intramuscular administration.The compositions are formulated in such a manner that the pH value,buffer capacity and titration basicity do not deviate very much from thephysiological values. These injection compositions withstandsterilization in an autoclave for 20 minutes at 121° C. without anychemical change taking place.

EXAMPLE

    ______________________________________                                        1-allyl-2-cyanoaziridine                                                                     40 mg.   40 mg.   40 mg.                                                                              40 mg.                                 polyethylene glycol 400                                                                      1 mg.                                                          water          3 mg.    3 mg.    4 mg.                                        ethylene glycol mono-   2 mg.    1 mg.                                        ethyl ether                                                                   "Miglycol" 812 neutral oil             3 mg.                                  ethanol        1 mg.                                                          ______________________________________                                    

The solvents are mixed together with the active material in a kettle.The solution thus obtained is sterilized by filtration through filterlayers of Fibrafix AF. The first 15 liters are pre-runnings which arerecycled to the batch. The membrane filtration is carried out directlyon a filling machine via a Sartorius membrane filter of 0.2 μm. poresize. The solution is subsequently filled in 5 ml. ampoules and thensterilized in an autoclave for 20 minutes at 121° C.

EXAMPLE C (Soft Gelatine Capsules)

The active material is soluble in organic compounds, such as "Miglyol"812 (triglyceride of saturated fatty acids with a chain length of C=30),mixtures of ethanol in water, polyethylene glycol 400 in water andethylene glycol monoethyl ether in water and can, in such solutions, beworked up to give soft gelatine capsules. The active material can alsobe worked up in admixture with wax, soya bean oil, lecithin andhydrogenated fats to give a conventional soft gelatine formulation.

EXAMPLE

    ______________________________________                                        1-Allyl-2-                                                                            40 mg.   40 mg.   40 mg. 40 mg. 40 mg.                                cyano-                                                                        aziridine                                                                     bees' wax                                                                             20 mg.                                                                hydro-  140 mg.                                                               genated                                                                       soya bean                                                                     oil                                                                           soya    70 mg.                                                                lecithin                                                                      poly-            210 mg.                180 mg.                               ethylene                                                                      glycol 400                                                                    "Miglyol"        100 mg.  100 mg.                                                                              200 mg.                                                                              35 mg.                                812                                                                           ethylene                  210 mg.                                                                              50 mg.                                       glycol                                                                        monoethyl                                                                     ether                                                                         ethyl                            43 mg. 85 mg.                                acetate                                                                       ______________________________________                                    

the active material can be mixed with the appropriate amounts of theabove-mentioned adjuvants and worked up on a special machine to givesoft gelatine capsules of various sizes and dosages.

EXAMPLE D (Drops and Syrups)

    __________________________________________________________________________    (a)                                                                             1-allyl-2-cyano                                                                        2.5 ml.                                                                            2.5 ml.                                                                            2.5 ml.                                                                            2.5 ml.                                                                            2.5 ml.                                                                            2.5 ml.                                     aziridine                                                                     polyethylene                                                                           --   9.5 ml.                                                                            10.5 ml.                                                                           7.5 ml.                                                                            --   7.5 ml.                                     glycol 400                                                                    ethyl acetate                                                                          --   8.0 ml.                                                                            5.0 ml.                                                                            --   2.5 ml.                                                                            --                                          ethylene glycol                                                                        12.0 ml.                                                                           --   --   9.0 ml.                                                                            3.0 ml.                                                                            3.0 ml.                                     monomethyl ether                                                              "Miglyol" 812                                                                          5.5 ml.                                                                            --   2.0 ml.                                                                            1.0 ml.                                                                            12.0 ml.                                         water                             7.0 ml.                                   (b)                                                                             1-Allyl-2-cyano-                                                                       2.5 ml.                                                                            2.5 ml.                                                                            2.5 ml.                                                                            2.5 ml.                                               aziridine                                                                     polyethylene                                                                           --   --   12.0 ml.                                                                           --                                                    glycol 400                                                                    ethylene glycol                                                                        2.0 ml.                                                                            --   --   52.0 ml.                                              monoethyl ether                                                               ethyl acetate                                                                          --   --   --   43.0 ml.                                              "Miglyol" 812                                                                          --   154.0 ml.                                                                          --   80.0 ml.                                              water    134.0 ml. 143.0 ml.                                                __________________________________________________________________________

The active material is mixed with appropriate amounts of theabove-mentioned adjuvants. The mixture is sterilized by means of filterlayers of Fibrafix AF and also filtered through membrane filters with apore size of 0.2 μm., followed by filling into 20 ml. drop bottles orinto 200 ml. syrup bottles.

The present invention also provides pharmaceutical compositionscomprising the new compound and/or at least one solid or liquidpharmaceutical diluent or carrier.

For the preparation of pharmaceutical compositions, an N-substitutedaziridine-2-carboxylic acid derivative the invention is mixed in knownmanner with an appropriate pharmaceutical carrier substance and formed,for example, into tablets or dragees or, with the addition ofappropriate adjuvants, suspended or dissolved in water or an oil, forexample olive oil, and placed in capsules. Since the active material isacid labile, the composition is provided with a coating which onlydissolves in the alkaline medium of the intestines or an appropriatecarrier material, for example a high molecular weight fatty acid orcarboxymethyl-cellulose is mixed therewith. Examples of solid carriermaterials include starch, lactose, mannitol, methyl cellulose, talc,highly dispersed silicic acids, high molecular weight fatty acids (forexample stearic acid), gelatin, agar-agar, calcium phosphate, magnesiumstearate, animal and vegetable fats and solid high molecular weightpolymers (such as polyethylene glycols). Compositions suitable for oraladministration can, if desired, contain flavoring and/or sweeteningmaterials.

However, the active material is preferably injected. As injectionmedium, it is preferred to use water which contains the additives usualin the case of injection solutions, such as stabilizing agents,solubilizing agents and/or weakly alkaline buffers. Additives of thistype include, for example, phosphate and carbonate buffers, ethanol,complex-forming agents (for example ethylenediamine-tetraacetic acid andthe non-toxic salts thereof) and high molecular weight polymers (forexample liquid polyethylene oxide) for viscosity regulation.

For treatment of humans the active material may be applied one or moretimes with each dose containing about 25 to 3000 and preferably 50 to500 mg of active material.

It will be appreciated that the instant specification and examples areset forth by way of illustration and not limitation, and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention.

We claim:
 1. A 2-cyanaziridine derivative of the formula ##STR12##wherein R' is a straight-chained or branched, saturated or mono- orpolyunsaturated aliphatic hydrocarbon radical with up to 8 carbon atoms,which is substituted by a pyridine or pyrimidine radical optionallysubstituted by halogen, alkoxy with up to 8 carbon atoms, alkyl with upto 8 carbon atoms, hydroxyl, carbalkoxy with up to 9 carbon atoms,carbamoyl, dialkylamino the alkyl moieties of which having up to 8carbon atoms, cycloalkylamino, the cycloalkyl moiety having 3-10 carbonatoms, acetylamino, nitro, cyano, acetyl, alkylthio with up to 8 carbonatoms, alkylsulphinyl with up to 8 carbon atoms, alkylsulphonyl with upto 8 carbon atoms, sulphamoyl, phenyl, trifluoromethyl, phenoxy, acetoxyor methylenedioxy;or a pharmacologically acceptable salt thereof.
 2. Acompound according to claim 1, wherein such compound is2-cyano-1-(5-methylpyrimidin-4-ylmethyl)-aziridine of the formula##STR13## or a pharmacologically acceptable acid addition salt thereof.3. A compound according to claim 1, wherein such compound is2-cyano-1-[(2-methoxy-6-methylpyridin-3-yl)-methyl]-aziridine of theformula ##STR14## or a pharmacologically acceptable acid addition saltthereof.
 4. An immuno-stimulating composition comprising animmuno-stimulating effective amount of an aziridine-2-carboxylic acidderivative as defined in claim 1 and a pharmacologically acceptablediluent.
 5. A method of stimulating an immune response in a patientwhich comprises administering to the patient an immunostimulatingeffective amount of a 2-cyanaziridine derivative or salt thereofaccording to claim
 1. 6. The method according to claim 5, wherein suchderivative is2-cyano-1-(5-methylpyrimidin-4-ylmethyl)aziridine or2-cyano-1-[(2-methoxy-6-methylpyrimidin-3-yl)methyl]-aziridine,or apharmacologically acceptable salt thereof.